Mutanobactin D from the Human Microbiome: Total Synthesis, Configurational Assignment, and Biological Evaluation

Abstract

Mutanobactin D is a non-ribosomal, cyclic peptide isolated from Streptococcus mutans and shows activity reducing yeast-to-hyphae transition as well as biofilm formation of the pathogenic yeast Candida albicans. We report the first total synthesis of this natural product, which relies on enantioselective, zinc-mediated 1,3-dipolar cycloaddition and a sequence of cascading reactions, providing the key lipidated γ-amino acid found in mutanobactin D. The synthesis enables configurational assignment, determination of the dominant solution-state structure, and studies to assess the stability of the lipopeptide substructure found in the natural product. The information stored in the fingerprint region of the IR spectra in combination with quantum chemical calculations proved key to distinguishing between epimers of the α-substituted β-keto amide. Synthetic mutanobactin D drives discovery and analysis of its effect on growth of other members of the human oral consortium. Our results showcase how total synthesis is central for elucidating the complex network of interspecies communications of human colonizers.

Δ-Quantum machine-learning for medicinal chemistry

“…effects may also be anticipated in medicinal chemistry as the electronic structure of drug-like molecules governs many related properties. Potential examples include the influence of (i) HOMO/LUMO energies on phototoxicity, 4,5 (ii) dipole moments on aqueous solubility 78,79 and membrane permeability, 9,80 and (iii) formation energies on 3D-conformer ensembles 9 or site-of-metabolism prediction. 81 Future prospective applications will reveal the practical applicability and usefulness of these models in drug discoveryrelated tasks.…”

“…The electronic structure of drug-like molecules is responsible for various drug-relevant properties, such as molecular recognition in protein-ligand complexes, [1][2][3] drug-induced phototoxicity, 4,5 reactivity for covalent ligand-protein interaction, [6][7][8] cell membrane permeability, 9 or three-dimensional (3D) conformation energies. 10 However, despite advances in density functional theory (DFT) approaches, 11,12 which are widely regarded as a compromise between accuracy and computational cost, 13,14 calculating quantum-mechanical (QM) properties at this level of theory for many or for sizable molecules remains a computationally expensive task.…”

Time-Resolved Atomistic Imaging and Statistical Analysis of Daptomycin Oligomers with and without Calcium Ions

“…Figure a) . Like many other medium-sized peptides and related molecules, − the crystal structure of this flexible peptide or their aggregates has yet to become available. The consensus mechanism invokes selective DP binding on the Ca 2+ -rich phosphatidylglycerol membrane, triggering assembly into a tetramer or larger oligomers as administered at the μg/mL level.…”

Δ-Quantum machine learning for medicinal chemistry

“…The electronic structure of drug-like molecules is responsible for various drug-relevant properties, such as molecular recognition in protein-ligand complexes [1][2][3] , drug-induced photo-toxicity 4,5 , reactivity for covalent ligand-protein interaction [6][7][8] , cell membrane permeability 9 , or three-dimensional (3D) conformation energies 10 . However, despite advances in density functional theory (DFT) approaches 11,12 , which are widely regarded as a compromise between accuracy and computational cost 13,14 , calculating quantum-mechanical (QM) properties at this level of theory for many or for sizable molecules remains a computationally expensive task.…”